title: Evolutionary dynamics of cancer in response to targeted combination therapy.
abstract: In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI:http://dx.doi.org/10.7554/eLife.00747.001.
authors.affiliation: Program for Evolutionary Dynamics , Harvard University , Cambridge , United States ; Department of Mathematics , Harvard University , Cambridge , United States.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Reiter
authors.forename: Benjamin
authors.initials: B
authors.lastname: Allen
authors.forename: Tibor
authors.initials: T
authors.lastname: Antal
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chatterjee
authors.forename: Preya
authors.initials: P
authors.lastname: Shah
authors.forename: Yo Sup
authors.initials: YS
authors.lastname: Moon
authors.forename: Amin
authors.initials: A
authors.lastname: Yaqubie
authors.forename: Nicole
authors.initials: N
authors.lastname: Kelly
authors.forename: Dung T
authors.initials: DT
authors.lastname: Le
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Lipson
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019143:Evolution, Molecular; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics
keywords: None; cancer; genetics; mathematical biology; stochastic processes; targeted therapy